Meta-substituted phenylene sulphonamide derivatives

ABSTRACT

The present invention relates to a class of compounds represented by the Formula I  
                 
 
or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula I, and methods of selectively inhibiting or antagonizing the α v β 3  integrin.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical agents (compounds) whichare useful as α_(v)β₃ integrin antagonists or inhibitors and as such areuseful in pharmaceutical compositions and in methods for treatingconditions mediated by α_(v)β₃ by inhibiting or antagonizing α_(v)β₃integrins.

BACKGROUND OF THE INVENTION

Integrins are a group of cell surface glycoproteins which mediate celladhesion and therefore are useful mediators of cell adhesioninteractions which occur during various biological processes. Integrinsare heterodimers composed of noncovalently linked α and β polypeptidesubunits. Currently eleven different α subunits have been identified andsix different β subunits have been identified. The various α subunitscan combine with various β subunits to form distinct integrins.

The integrin identified as α_(v)β₃ (also known as the vitronectinreceptor) has been identified as an integrin which plays a role invarious conditions or disease states including tumor metastasis, solidtumor growth (neoplasia), osteoporosis, Paget's disease, humoralhypercalcemia of malignancy, angiogenesis, including tumor angiogenesis,retinopathy, arthritis, including rheumatoid arthritis, periodontaldisease, psoriasis and smooth muscle cell migration (e.g. restenosis).Additionally, it has been found that such agents would be useful asantivirals, antifungals and antimicrobials. Thus, compounds whichselectively inhibit or antagonize α_(v)β₃ would be beneficial fortreating such conditions.

It has been shown that the α_(v)β₃ integrin and other α_(v) containingintegrins bind to a number of Arg-Gly-Asp (RGD) containing matrixmacromolecules. Compounds containing the RGD sequence mimicextracellular matrix ligands so as to bind to cell surface receptors.However, it is also known that RGD peptides in general are non-selectivefor RGD dependent integrins. For example, most RGD peptides which bindto α_(v)β₃ also bind to α_(v)β₅, α_(v)β₁ and α_(IIb)β₃. Antagonism ofplatelet α_(IIb)β₃ (also known as the fibrinogen receptor) is known toblock platelet aggregation in humans. In order to avoid bleedingside-effects when treating the conditions or disease states associatedwith the integrin α_(v)β₃, it would be beneficial to develop compoundswhich are selective antagonists of α_(v)β₃ as opposed to α_(IIb)β₃.

Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561)have shown that the α_(v)β₃ integrin has a biological function inmelanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA,Vol. 91 (1994) 8856-60) have demonstrated that the integrin α_(v)β₃expressed on human melanoma cells promotes a survival signal, protectingthe cells from apoptosis. Mediation of the tumor cell metastatic pathwayby interference with the α_(v)β₃ integrin cell adhesion receptor toimpede tumor metastasis would be beneficial.

Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated thatantagonists of α_(v)β₃ provide a therapeutic approach for the treatmentof neoplasia (inhibition of solid tumor growth) since systemicadministration of α_(v)β₃ antagonists causes dramatic regression ofvarious histologically distinct human tumors.

The adhesion receptor integrin α_(v)β₃ was identified as a marker ofangiogenic blood vessels in chick and man and therefore such receptorplays a critical role in angiogenesis or neovascularization.Angiogenesis is characterized by the invasion, migration andproliferation of smooth muscle and endothelial cells. Antagonists ofα_(v)β₃ inhibit this process by selectively promoting apoptosis of cellsin neovasculature. The growth of new blood vessels, or angiogenesis,also contributes to pathological conditions such as diabetic retinopathy(Adonis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) andrheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992),1135-1138). Therefore, α_(v)β₃ antagonists would be useful therapeutictargets for treating such conditions associated with neovascularization(Brooks et al., Science, Vol. 264, (1994), 569-571).

It has been reported that the cell surface receptor α_(v)β₃ is the majorintegrin on osteoclasts responsible for attachment to bone. Osteoclastscause bone resorption and when such bone resorbing activity exceeds boneforming activity it results in osteoporosis (a loss of bone), whichleads to an increased number of bone fractures, incapacitation andincreased mortality. Antagonists of α_(v)β₃ have been shown to be potentinhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell.Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al.,Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of α_(v)β₃ leadsto decreased bone resorption and therefore restores a normal balance ofbone forming and resorbing activity. Thus it would be beneficial toprovide antagonists of osteoclast α_(v)β₃ which are effective inhibitorsof bone resorption and therefore are useful in the treatment orprevention of osteoporosis.

The role of the α_(v)β₃ integrin in smooth muscle cell migration alsomakes it a therapeutic target for prevention or inhibition of neointimalhyperplasia which is a leading cause of restenosis after vascularprocedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34).Prevention or inhibition of neointimal hyperplasia by pharmaceuticalagents to prevent or inhibit restenosis would be beneficial.

White (Current Biology, Vol. 3(9)(1993) 596-599) has reported thatadenovirus uses α_(v)β₃ for entering host cells. The integrin appears tobe required for endocytosis of the virus particle and may be requiredfor penetration of the viral genome into the host cell cytoplasm. Thuscompounds which inhibit α_(v)β₃ would find usefulness as antiviralagents.

SUMMARY OF THE INVENTION

The present invention relates to a class of compounds represented by theFormula I

or a pharmaceutically acceptable salt thereof, wherein

B is selected from the group consisting of —CONR⁵⁰— and —SO₂NR⁵⁰—;

A is

wherein Y¹ is selected from the group consisting of N—R², O, and S;

R² is selected from the group consisting of H; alkyl; aryl; hydroxy;alkoxy; cyano; nitro; amino; alkenyl; alkynyl; alkyl optionallysubstituted with one or more substituent selected from lower alkyl,halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy,aryl or aryl optionally substituted with one or more halogen, haloalkyl,lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl,amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles, or fused monocyclic heterocycles; aryloptionally substituted with one or more substituent selected fromhalogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy,ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid,sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclicheterocycles and fused monocyclic heterocycle; monocyclic heterocycles;and monocyclic heterocycles optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio,alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or

R² taken together with R⁷ forms a 4-12 membered dinitrogen containingheterocycle optionally substituted with one or more substituent selectedfrom the group consisting of lower alkyl, hydroxy and phenyl;

or R² taken together with R⁷ forms a 5 membered heteroaromatic ring;

or R² taken together with R⁷ forms a 5 membered heteroaromatic ringfused with a phenyl group;

R⁷ (when not taken together with R²) and R⁸ are independently selectedfrom the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl;cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionallysubstituted with one or more substituent selected from lower alkyl,halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino,alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles, fused monocyclic heterocycles; aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fusedmonocyclic heterocycles; monocyclic heterocycles; monocyclicheterocycles optionally substituted with one or more substituentselected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino,nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl,aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; —SO₂R¹⁰wherein R¹⁰ is selected from the group consisting of alkyl, aryl andmonocyclic heterocycles, all optionally substituted with one or moresubstituent selected from the group consisting of halogen, haloalkyl,alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido,alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino,dialkylamino, trifluoromethylthio, trifluoroalkoxy,trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclicheterocycles; and

wherein R¹⁰ is defined above;or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogencontaining monocyclic or bicyclic ring optionally substituted with oneor more substituent selected from lower alkyl, carboxyl derivatives,aryl or hydroxy and wherein said ring optionally contains a heteroatomselected from the group consisting of O, N and S;

R⁵ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,benzyl, and phenethyl;

or

A is

wherein Y² is selected from the group consisting of H, alkyl;cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles; alkyloptionally substituted with aryl which can also be optionallysubstituted with one or more substituent selected from halo, haloalkyl,alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryloptionally substituted with one or more substituent selected from halo,haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro,methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; —S—R⁹ and—O—R⁹ wherein R⁹ is selected from the group consisting of H; alkyl;aralkyl; aryl; alkenyl; and alkynyl; or R⁹ taken together with R⁷ formsa 4-12 membered mononitrogen containing sulfur or oxygen containingheterocyclic ring; and

R⁵ and R⁷ are as defined above;

or Y² (when Y² is carbon) taken together with R⁷ forms a 4-12 memberedmononitrogen containing ring optionally substituted with alkyl, aryl orhydroxy;

Z¹, Z², Z⁴ and Z⁵ are independently selected from the group consistingof H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl;haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano;alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fusedaryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclicheterocycles; and A, wherein A is defined above;

R⁵⁰ is selected from the group consisting of H and alkyl;

R¹ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,aryl and aryl, optionally substituted with one or more substituentselected from the group consisting of halogen, haloalkyl, hydroxy,alkoxy, aryloxy, aralkoxy, amino, aminoalkyl, carboxyl derivatives,cyano and nitro;

t is an integer 0, 1 or 2;

R is X—R³ wherein X is selected from the group consisting of O, S andNR⁴, wherein R³ and R⁴ are independently selected from the groupconsisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl;arylalkyl; sugars; steroids and in the case of the free acid, allpharmaceutically acceptable salts thereof; and

Y³ and Z³ are independently selected from the group consisting of H,alkyl, aryl, cycloalkyl and aralkyl.

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ integrin and therefore in another embodiment the presentinvention relates to a method of selectively inhibiting or antagonizingthe α_(v)β₃ integrin. The invention further involves treating orinhibiting pathological conditions associated therewith such asosteoporosis, humoral hypercalcemia of malignancy, Paget's disease,tumor metastasis, solid tumor growth (neoplasia), angiogenesis,including tumor angiogenesis, retinopathy including diabeticretinopathy, arthritis, including rheumatoid arthritis, periodontaldisease, psoriasis, smooth muscle cell migration and restenosis in amammal in need of such treatment. Additionally, such pharmaceuticalagents are useful as antiviral agents, and antimicrobials.

DETAILED DESCRIPTION

The present invention relates to a class of compounds represented by theFormula I, described above.

A preferred embodiment of the present invention is a compound of theFormula II

Another preferred embodiment of the present invention is a compound ofthe Formula III

The invention further relates to pharmaceutical compositions containingtherapeutically effective amounts of the compounds of Formulas I-III.

The invention also relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ integrin and more specifically relates to amethod of inhibiting bone resorption, periodontal disease, osteoporosis,humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis,solid tumor growth (neoplasia), angiogenesis, including tumorangiogenesis, retinopathy including diabetic retinopathy, arthritis,including rheumatoid arthritis, smooth muscle cell migration andrestenosis by administering a therapeutically effective amount of acompound of the Formula I-III to achieve such inhibition together with apharmaceutically acceptable carrier.

The following is a list of definitions of various terms used herein:

As used herein, the terms “alkyl” or “lower alkyl” refer to a straightchain or branched chain hydrocarbon radicals having from about 1 toabout 10 carbon atoms, and more preferably 1 to about 6 carbon atoms.Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl,isohexyl, and the like.

As used herein the terms “alkenyl” or “lower alkenyl” refer tounsaturated acyclic hydrocarbon radicals containing at least one doublebond and 2 to about 6 carbon atoms, which carbon-carbon double bond mayhave either cis or trans geometry within the alkenyl moiety, relative togroups substituted on the double bond carbons. Examples of such groupsare ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and thelike.

As used herein the terms “alkynyl” or “lower alkynyl” refer to acyclichydrocarbon radicals containing one or more triple bonds and 2 to about6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

The term “cycloalkyl” as used herein means saturated or partiallyunsaturated cyclic carbon radicals containing 3 to about 8 carbon atomsand more preferably 4 to about 6 carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.

The term “aryl” as used herein denotes aromatic ring systems composed ofone or more aromatic rings. Preferred aryl groups are those consistingof one, two or three aromatic rings. The term embraces aromatic radicalssuch as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and thelike.

As used herein, the term “cyano” is represented by a radical of theformula

The terms “hydroxy” and “hydroxyl” as used herein are synonymous and arerepresented by a radical of the formula

The term “lower alkylene” or “alkylene” as used herein refers todivalent linear or branched saturated hydrocarbon radicals of 1 to about6 carbon atoms.

As used herein the term “alkynylene” or “lower alkynylene” refers to analkylene radical wherein at least one bond between the carbon atoms isunsaturated and such unsaturation forms a triple bond.

As used herein the term “alkenylene” or “lower alkenylene” refers to analkylene radical wherein at least one bond between the carbon atoms isunsaturated and such unsaturation produces a double bond in cis ortransconformation.

As used herein the term “alkoxy” refers to straight or branched chainoxy containing radicals of the formula —OR²⁰, wherein R²⁰ is an alkylgroup as defined above. Examples of alkoxy groups encompassed includemethoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy,t-butoxy and the like.

As used herein the terms “arylalkyl” or “aralkyl” refer to a radical ofthe formula

wherein R²¹ is aryl as defined above and R²² is an alkylene as definedabove. Examples of aralkyl groups include benzyl, pyridylmethyl,naphthylpropyl, phenethyl and the like.

As used herein the term “aralkoxy” or “arylakoxy” refers to a radical ofthe formula

wherein R⁵³ is aralkyl as defined above.

As used herein the term “nitro” is represented by a radical of theformula

As used herein the term “halo” or “halogen” refers to bromo, chloro,fluoro or iodo.

As used herein the term “haloalkyl” refers to alkyl groups as definedabove substituted with one or more of the same or different halo groupsat one or more carbon atom. Examples of haloalkyl groups includetrifluoromethyl, dichloroethyl, fluoropropyl and the like.

As used herein the term “carboxyl” or “carboxy” refers to a radical ofthe formula —COOH.

As used herein the term aminoalkyl” refers to a radical of the formula—R⁵⁴—NH₂ wherein R⁵⁴ is lower alkylene as defined above.

As used herein the term “carboxyl derivative” refers to a radical of theformula

wherein Y⁶ and Y⁷ are independently selected from the group consistingof O, N or S and R²³ is selected from the group consisting of H, alkyl,aralkyl or aryl as defined above.

As used herein the term “amino” is represented by a radical of theformula —NH₂.

As used herein the term “alkylsulfonyl” or “alkylsulfone” refers to aradical of the formula

wherein R²⁴ is alkyl as defined above.

As used herein the term “alkylthio” refers to a radical of the formula—SR²⁴ wherein R²⁴ is alkyl as defined above.

As used herein the term “sulfonic acid” refers to a radical of theformula

wherein R²⁵ is H, alkyl or aryl as defined above.

As used herein the term “sulfonamide” refers to a radical of the formula

wherein R⁷ and R⁸ are as defined above.

As used herein the term “fused aryl” refers to an aromatic ring such asthe aryl groups defined above fused to one or more phenyl rings.Embraced by the term “fused aryl” is the radical naphthyl.

As used herein the terms “monocyclic heterocycle” or “monocyclicheterocyclic” refer to a monocyclic ring containing from 4 to about 12atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 ofthe atoms are heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur with the understanding that if two or more differentheteroatoms are present at least one of the heteroatoms must benitrogen. Representative of such monocyclic heterocycles are imidazole,furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole,thiazole, thiadiazole, and the like.

As used herein the term “fused monocyclic heterocycle” refers to amonocyclic heterocycle as defined above with a benzene fused thereto.Examples of such fused monocyclic heterocycles include benzofuran,benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazoleand the like.

As used herein the term “methylenedioxy” refers to the radical

and the term “ethylenedioxy” refers to the radical

As used herein the term “4-12 membered dinitrogen containing heterocyclerefers to a radical of the formula

wherein m is 1 or 2 and R¹⁹ is H, alkyl, aryl, or aralkyl and morepreferably refers to 4-9 membered ring and includes rings such asimidazoline.

As used herein the term “5-membered heteroaromatic ring” includes forexample a radical of the formula

and “5-membered heteroaromatic ring fused with a phenyl” refers to sucha “5-membered heteroaromatic ring” with a phenyl fused thereto.Representative of such 5-membered heteroaromatic rings fused with aphenyl is benzimidazole.

As used herein the term “bicycloalkyl” refers to a bicyclic hydrocarbonradical containing 6 to about 12 carbon atoms which is saturated orpartially unsaturated.

As used herein the term “acyl” refers to a radical of the formula

wherein R²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl as definedabove. Encompassed by such radical are the groups acetyl, benzoyl andthe like.

As used herein the term “thio” refers to a radical of the formula

As used herein the term “sulfonyl” refers to a radical of the formula

wherein R²⁷ is alkyl, aryl or aralkyl as defined above.

As used herein the term “haloalkylthio” refers to a radical of theformula —S—R²⁸ wherein R²⁸ is haloalkyl as defined above.

As used herein the term “aryloxy” refers to a radical of the formula

wherein R²⁹ is aryl as defined above.

As used herein the term “acylamino” refers to a radical of the formula

wherein R³⁰ is alkyl, aralkyl or aryl as defined above.

As used herein the term “amido” refers to a radical of the formula

wherein R³¹ is a bond or alkylene as defined above.

As used herein the term “alkylamino” refers to a radical of the formula—NHR³² wherein R³² is alkyl as defined above.

As used herein the term “dialkylamino” refers to a radical of theformula —NR³³R³⁴ wherein R³³ and R³⁴ are the same or different alkylgroups as defined above.

As used herein the term “trifluoromethyl” refers to a radical of theformula

As used herein the term “trifluoroalkoxy” refers to a radical of theformula

wherein R³⁵ is a bond or an alkylene as defined above.

As used herein the term “alkylaminosulfonyl” refers to a radical of theformula

wherein R³⁶ is alkyl as defined above.

As used herein the term “alkylsulfonylamino” refers to a radical of theformula

wherein R³⁶ is alkyl as defined above.

As used herein the term “trifluoromethylthio” refers to a radical of theformula

As used herein the term “trifluoromethylsulfonyl” refers to a radical ofthe formula

As used herein the term “4-12 membered mono-nitrogen containingmonocyclic or bicyclic ring” refers to a saturated or partiallyunsaturated monocyclic or bicyclic ring of 4-12 atoms and morepreferably a ring of 4-9 atoms wherein one atom is nitrogen. Such ringsmay optionally contain additional heteroatoms selected from nitrogen,oxygen or sulfur. Included within this group are morpholine, piperidine,piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene andthe like.

As used herein the term “benzyl” refers to the radical

As used herein the term “phenethyl” refers to the radical

As used herein the term “4-12 membered mono-nitrogen containing sulfuror oxygen containing heterocyclic ring” refers to a ring consisting of 4to 12 atoms and more preferably 4 to 9 atoms wherein at least one atomis a nitrogen and at least one atom is oxygen or sulfur. Encompassedwithin this definition are rings such as thiazoline and the like.

As used herein the term “arylsulfonyl” or “arylsulfone” refers to aradical of the formula

wherein R³⁷ is aryl as defined above.

As used herein the terms “alkylsulfoxide” or “arylsulfoxide” refer toradicals of the formula

wherein R³⁸ is, respectively, alkyl or aryl as defined above.

As used herein the term “phosphonic acid derivative” refers to a radicalof the formula

wherein R³⁹ and R⁴⁰ are the same or different H, alkyl, aryl or aralkyl.

As used herein the term “phosphinic acid derivatives” refers to aradical of the formula

wherein R⁴¹ is H, alkyl, aryl or aralkyl as defined above.

As used herein the term “arylthio” refers to a radical of the formula

wherein R⁴² is aryl as defined above.

As used herein the term “monocyclic heterocycle thio” refers to aradical of the formula

wherein R⁴³ is a monocyclic heterocycle radical as defined above.

As used herein the terms “monocyclic heterocycle sulfoxide” and“monocyclic heterocycle sulfone” refer, respectively, to radicals of theformula

and

wherein R⁴³ is a monocyclic heterocycle radical as defined above.

The term “composition” as used herein means a product which results fromthe mixing or combining of more than one element or ingredient.

The term “pharmaceutically acceptable carrier”, as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a chemical agent.

The term “therapeutically effective amount” shall mean that amount ofdrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system or animal that is being sought by aresearcher or clinician.

The following is a list of abbreviations and the corresponding meaningsas used interchangeably herein:

¹H-NMR=proton nuclear magnetic resonance

AcOH=acetic acid

BH₃-THF=borane-tetrahydrofuran complex

BOC=tert-butoxycarbonyl

Cat.=catalytic amount

CH₂Cl₂=dichloromethane

CH₃CN=acetonitrile

CH₃I=iodomethane

CHN analysis=carbon/hydrogen/nitrogen elemental analysis

CHNCl analysis=carbon/hydrogen/nitrogen/chlorine elemental analysis

CHNS analysis=carbon/hydrogen/nitrogen/sulfur elemental analysis

DCC=1,3-dicyclohexylcarbodiimide

DIEA=diisopropylethylamine

DMA=N,N-dimethylacetamide

DMAC=Dimethylacetamide

DMAP=4-(N,N-dimethylamino)pyridine

DMF=N,N-dimethylformamide

DSC=disuccinyl carbonate

EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Et₂O=diethyl ether

Et₃N=triethylamine

EtOAc=ethyl acetate

EtOH=ethanol

FAB MS=fast atom bombardment mass spectroscopy

g=gram(s)

GIHA HCl=meta-guanidino-hippuric acid hydrochloride

GIHA=meta-guanidino-hippuric acid

HPLC=high performance liquid chromatography

IBCF=isobutylchloroformate

K₂CO₃=potassium carbonate

KOH=potassium hydroxide

LiOH=lithium hydroxide

MCPBA=m-chloroperoxybenzoic acid or m-chloroperbenzoic acid

MeOH=methanol

MesCl=methanesulfonylchloride

mg=milligram

MgSO₄=magnesium sulfate

ml=milliliter

mL=milliliter

MS=mass spectroscopy

N₂=nitrogen

NaCNBH₃=sodium cyanoborohydride

Na₂PO₄=sodium phosphate

Na₂SO₄=sodium sulfate

NaHCO₃=sodium bicarbonate

NaOH=sodium hydroxide

NH₄HC0₃=ammonium bicarbonate

NH₄ ⁺HCO₂ ⁻=ammonium formate

NMM=N-methyl morpholine

NMR=nuclear magnetic resonance

RPHPLC=reverse phase high performance liquid chromatography

RT=room temperature

KSCN=potassium thiocyanate

Pd/C=palladium on carbon

Bn=benzyl

Et=ethyl

Me=methyl

Ph=phenyl

NEt₃=triethylamine

t-BOC=tert-butoxycarbonyl

TFA=trifluoroacetic acid

THF=tetrahydrofuran

Δ=heating the reaction mixture

As used herein HPLC-Method 1 refers to reverse phase C-18 functionalizedsilica gel column (50×300 mm) using a linear gradient of 95% 0.6%TFA/water: 5% CH₃CN to 60% 0.6% TFA/water: 40% CH₃CN with a flow rate of80 ml/minute.

The compounds as shown in Formulas I-III can exist in various isomericforms and all such isomeric forms are meant to be included. Tautomericforms are also included as well as pharmaceutically acceptable salts ofsuch isomers and tautomers.

In the structures and formulas herein, a bond drawn across a bond of aring can be to any available atom on the ring.

The term “pharmaceutically acceptable salt” refers to a salt prepared bycontacting a compound of Formula I with an acid whose anion is generallyconsidered suitable for human consumption. Examples of pharmacologicallyacceptable salts include the hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, acetate, propionate, lactate, maleate, malate,succinate, tartrate salts and the like. All of the pharmacologicallyacceptable salts may be prepared by conventional means. (See Berge etal., J Pharm. Sci., 66(1), 1-19 (1977) for additional examples ofpharmaceutically acceptable salts.)

For the selective inhibition or antagonism of α_(v)β₃ integrins,compounds of the present invention may be administered orally,parenterally, or by inhalation spray, or topically in unit dosageformulations containing conventional pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereinincludes, for example, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitonally.

The compounds of the present invention are administered by any suitableroute in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds required to prevent orarrest the progress of or to treat the medical condition are readilyascertained by one of ordinary skill in the art using preclinical andclinical approaches familiar to the medicinal arts.

Accordingly, the present invention provides a method of treatingconditions mediated by selectively inhibiting or antagonizing theα_(v)β₃ cell surface receptor which method comprises administering atherapeutically effective amount of a compound selected from the classof compounds depicted in Formulas I-III, wherein one or more compoundsof the Formulas I-III is administered in association with one or morenon-toxic, pharmaceutically acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) andif desired other active ingredients. More specifically, the presentinvention provides a method for inhibition of the α_(v)β₃ cell surfacereceptor. Most preferably the present invention provides a method forinhibiting bone resorption, treating osteoporosis, inhibiting humoralhypercalcemia of malignancy, treating Paget's disease, inhibiting tumormetastasis, inhibiting neoplasia (solid tumor growth), inhibitingangiogenesis including tumor angiogenesis, treating diabeticretinopathy, inhibiting arthritis, psoriasis and periodontal disease,and inhibiting smooth muscle cell migration including restenosis.

Based upon standard laboratory experimental techniques and procedureswell known and appreciated by those skilled in the art, as well ascomparisons with compounds of known usefulness, the compounds of FormulaI can be used in the treatment of patients suffering from the abovepathological conditions. One skilled in the art will recognize thatselection of the most appropriate compound of the invention is withinthe ability of one with ordinary skill in the art and will depend on avariety of factors including assessment of results obtained in standardassay and animal models.

Treatment of a patient afflicted with one of the pathological conditionscomprises administering to such a patient an amount of compound of theFormula I which is therapeutically effective in controlling thecondition or in prolonging the survivability of the patient beyond thatexpected in the absence of such treatment. As used herein, the term“inhibition” of the condition refers to slowing, interrupting, arrestingor stopping the condition and does not necessarily indicate a totalelimination of the condition. It is believed that prolonging thesurvivability of a patient, beyond being a significant advantageouseffect in and of itself, also indicates that the condition isbeneficially controlled to some extent.

As stated previously, the compounds of the invention can be used in avariety of biological, prophylactic or therapeutic areas. It iscontemplated that these compounds are useful in prevention or treatmentof any disease state or condition wherein the α_(v)β₃ integrin plays arole.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 1000 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions and more preferably of the order from about0.01 mg to about 100 mg/kg of body weight.

The active ingredient administered by injection is formulated as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose would typically be about0.01 to 100 mg/kg body weight injected per day in multiple dosesdepending on the factors listed above and more preferably from about0.01 to about 10 mg/kg body weight.

For administration to a mammal in need of such treatment, the compoundsin a therapeutically effective amount are ordinarily combined with oneor more adjuvants appropriate to the indicated route of administration.The compounds may be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulphuric acids, gelatin, acacia, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tabletedor encapsulated for convenient administration. Alternatively, thecompounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

The pharmaceutical compositions useful in the present invention may besubjected to conventional pharmaceutical operations such assterilization and/or may contain conventional pharmaceutical adjuvantssuch as preservatives, stabilizers, wetting agents, emulsifiers,buffers, etc.

The general synthetic sequences for preparing the compounds useful inthe present invention are outlined in Schemes I-VI. Both an explanationof, and the actual procedures for, the various aspects of the presentinvention are described where appropriate. The following Schemes andExamples are intended to be merely illustrative of the presentinvention, and not limiting thereof in either scope or spirit. Those ofskill in the art will readily understand that known variations of theconditions and processes described in the Schemes and Examples can beused to perform the process of the present invention.

Unless otherwise indicated all starting materials and equipment employedwere commercially available.

Schemes I-VI are illustrative of methodology useful for preparingvarious compounds of the present invention. Such methodology is morespecifically defined in the examples which follow. Such methodology canbe modified by one skilled in the art, substituting known reagents andconditions from conventional methodology to produce the desiredcompounds.

Scheme I describes a synthesis of a pyridyl β-aminoacid which can beused to synthesize compounds of the present invention wherein R¹ ispyridyl. The reaction can be modified using conventional methodology toprepare other aromatic, alkyl or heterocyclic substituted β-amino acidsby substitution of the pyridyl carboxaldehyde with any other appropriatealdehyde. Briefly, in Scheme I to pyridine-carboxaldehyde in isopropanolis added ammonium acetate followed by malonic acid. The reaction mixtureis stirred at reflux, the resulting precipitate filtered and washed withhot isopropanol and dried to yield 3-amino-3-(3-pyridyl)propionic acid.The ethyl ester is synthesized by heating this acid in excess ethanol inthe presence of excess HCl gas.

Additionally, β-amino acids which are useful in the present inventionare accessible through modified Knoevenagel reactions (Secor, H. V.;Edwards, W. B. J. J. Org. Chem. 1979, 44, 3136-40; Bellasoued, M.;Arous-Chtar, R.; Gaudemar, M. J.; J. Organometal. Chem. 1982, 231,185-9), through Reformatski reaction with Schiff bases (Furukawa, M.;Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm. Bull. 1978, 26,260), Michael addition into an acrylic derivative (Davies, S. G.;Ichihara, O. Tetrahedron:Asymmetry 1991, 2, 183-6; Furukawa, M.;Okawara, T R.; Terawaki, Y. Chem. Pharm. Bull., 1977, 25, 1319-25). Morerecent methods include the use of organometallic reagents in Pd or Znmediated couplings (Konopelski, J.; Chu, K. S.; Negrete, G. R. J. Org.Chem. 1991, 56, 1355; Mokhallalati, M. K.; Wu, M-J.; Prigden, L. N.Tetrahedron Lett. 1993, 34, 47-50) to complement more traditionalreactions such as reductive amination of β-ketoesters.

The racemic beta-alkyl beta amino esters can also conveniently beprepared from the corresponding beta lactam by treatment with anhydrousHCl gas in ethanol. The beta lactams were prepared from thecorresponding alkene and chlorosulfonyl isocyanate (Szabo, W. A.Aldrichimica Acta, 1977, 23 and references cited therein). The lattermethod is useful for the preparation of α and β-substitutedβ-aminoacids. (Manhas, M. S.; Wagle, D. R.; Chong, J.; Bose, A. K.Heterocycles, 1988, 27, 1755.) Another route to α-substitutedβ-aminoacids is the Raney Nickel reduction of cyanoacetic esters attemperatures ranging between 20 and 80° C. and at 20 to 100 atm pressure(Testa, E.; Fontanella, L.; Fava, F. Fermaco Ed. Sci., 1958, 13, 152;Testa, E.; Fontanella, L. Annalen 1959, 625, 95). Also, a number ofprocedures are available for the preparation of β-aminoacids byreduction of hydrazones of keto-acids (Gottijes, J.; Nomte, W. Th. Rec.Trav. Chem. 1953, 72, 721), oximes (Anziegin, A.; Gulewivich, W. Z.Physiol. Chem., 1926, 158, 32) and nitropropionic acids. Purification offinal compounds is usually by reverse phase high performance liquidchromatography (RP HPLC) [High Performance Liquid Chromatography Proteinand Peptide Chemistry, F. Lottspeich, A. Henscher, K. P. Hupa, (eds.)Walter DeGruyter, New York, 1981] or crystallization.

Scheme III

For compounds wherein

-   1) R¹=CO₂H

(E) is the commercially available

-   2)    wherein    denotes an amino acid, the amino acid being protected with the    appropriate protecting groups.

Additional methodologies for further R¹ groups are as follows:

Scheme III (Cont'd)

In a similar manner, compounds of the present invention wherein R¹ issubstituted alkyl can be synthesized in the following manner:

Scheme IV represents the synthesis of aminohydrocoumarins (see J. Rico,Tett. Let., 1994, 35, 6599-6602) which are readily opened to form R¹being an orthohydroxyphenyl moiety, further substituted by Z¹.

Specifically, in Scheme V:

In the synthesis of intermediate benzoic acids (A1) through (A16), thestarting amino benzoic acids

are either commercially available or can be converted to such aminobenzoic acids via reduction of the corresponding nitro benzoic acid,which can be obtained commercially or syntheized by nitration of theappropriate benzoic acid, followed by reduction to the desired aminobenzoic acid. These are all when R⁵ is H. If R⁵ is other than H,alkylation of the amino functionality can be achieved by conventionalmethodology.

Furthermore, synthesis of intermediate (A2) can also be accomplished asdisclosed generally in U.S. Pat. No. 3,202,660, starting with theappropriate amino benzoic acid. Furthermore, intermediate (A2) and (A15)as well as further analogues of (A2) and (A15) such as substitutions onthe heterocyclic ring, oxazolidines, thiazolidines, benzimidazoles andthe like can also be accomplished as disclosed in

1) Chem. Pharm. Bull. 41(1) 117-125 (1993)

2) Chem. Pharm. Bull. 33(10) 4409-4421 (1985)

3) J. Med. Chem. 18 (1), 90-99 (1975).

used in the synthesis of intermediates (A3), can be synthesized from

and (Me)₃OBF₄ in dichloromethane.

HCl used in the synthesis of intermediate (A4), can be synthesized fromY²—CN and MeOH (1 equivalent) and HCl gas (1 equivalent) in heptane.

All other reagents in Scheme I are either commercially available orreadily synthesized by methodologies known by those skilled in the art.

When R⁵⁰ is not H, the appropriate nitrogen can be alkylated in anappropriate step by methodology known to those skilled in the art.Alternate acid derivatives R are synthesized by methodologies known tothose skilled in the art.

To synthesize compounds wherein

which is then treated in the same manner of further derivatization asexemplified in the previous schemes for:

Compounds of the present invention may be prepared as follows:

3-Nitrophenylsulphonylchloride B can be coupled to β-amino acids (asprepared in Schemes I-IV) to afford adduct C. Reduction of C (SnCl₂,EtOH, HCl, H₂O, 100°) affords aniline D. Aniline D can be coupled tointermediates (A1-16) as prepared in Scheme V using well known andstandard coupling procedures, followed by hydroylosis (or deprotection)of the resulting ester to afford compounds of the present invention.

EXAMPLE A 3-Guanidinobenzoic acid hydrochloride

To 3,5-dimethylpyrazole-1-carboxamidine nitrate (6 g, 0.03 mole)(Aldrich) and diisopropylamine (3.8 g, 0.03 mole) in dioxane (20 ml) andH₂O (10 ml) was added 3-aminobenzoic acid (2.7 g, 0.02 mole). Thereaction was stirred at reflux for 2.5 hours then overnight at roomtemperature. The resulting precipitate was filtered, washed withdioxane/H₂O and dried. The precipitate was then slurried in H₂O andacidified with concentrated HCl until a solution formed. The solvent wasremoved under vacuum and the residue was slurried twice in ether (etherdecanted off). The product was dried under vacuum to yield3-guanidinobenzoic acid hydrochloride (1.77 g) as a white solid. MS andNMR were consistent with the desired structure.

EXAMPLE B 3-(1-Aza-2-amino-1-cycloheptenyl)benzoic acid hydrochloride

To 1-aza-2-methoxy-1-cycloheptene (3.67 g, 0.0288 mole)(Aldrich) inabsolute ethanol (20 ml) was added 3-aminobenzoic acid hydrochloride (5g, 0.0288 mole). A solution quickly formed. The reaction mixture wasstirred overnight at room temperature. The resulting precipitate wasfiltered, washed with ether and dried under vacuum to yield3-(1-aza-2-amino-1-cycloheptene)-benzoic acid (4.9 g).

EXAMPLE C 3-(1-aza-2-amino-1-cycloheptenyl)-5-trifluoromethylbenzoicacid hydrochloride

The title compound was synthesized according to the methodology ofExample B, substituting an equivalent amount of3-amino-5-trifluoromethyl benzoic acid [which was synthesized byreduction of 3-nitro-5-trifluoromethyl benzoic acid (Lancaster) inethanol with 10% Pd/C under 50 psi H₂ for 4 hours] for 3-aminobenzoicacid.

EXAMPLE D 3-guanidino-5-trifluoromethylbenzoic acid, hydrochloride

The title compound was synthesized according to the methodology ofExample A, substituting an equivalent amount of3-amino-5-trifluoromethylbenzoic acid (see Example C) for 3-aminobenzoicacid.

EXAMPLE E

In a dried flask under nitrogen at 0° was dissolved 3-nitrobenzenesulfonyl chloride (2.2 g) (Aldrich) in methylene chloride (25 ml). Asolution of β-phenyl alanine ethyl ester hydrochloride (2.3 g),triethylamine (2.3 g) and methylene chloride (25 ml) was added at a rateso as not to allow the temperature to rise above 20°. The reactionmixture was stirred at room temperature for 1 hour and then partitionedbetween methylene chloride and water. The aqueous portion was extractedseveral times with additional methylene chloride and the combinedorganic extracts were washed with saturated sodium chloride solution,dried (Na₂SO₄), concentrated and purified on a silica gel column elutingwith 40% ethyl acetate −60% hexane to afford 3.3 g of white solid.

NMR was consistent with the proposed structure.

EXAMPLE F

A solution of the product from Example E (3.2 g) in dimethyl formamide(30 ml) was hydrogenated under a hydrogen atmosphere at room temperaturefor 16 hours using 4% palladium on carbon (300 mg). The reaction mixturewas concentrated and purified on a silica gel column using 1:1 ethylacetate:hexane as eluant to afford 1.6 g of a viscous golden oil. NMRwas consistent with the proposed structure.

EXAMPLE G

To a solution of 3-bis-boc-guanidine benzoic acid (266 mg) andN-methylmorpholine (76 mg) (Fluka) in DMF (3 ml) at 0° under nitrogenwas added a solution of isobutylchloroformate (96 mg) (Aldrich) in DMF(2 ml) in one portion.

The reaction mixture was stirred for 30 minutes and then a solution ofthe product from Example F (250 mg) and DMF (2 ml) was added in oneportion. The reaction mixture was stirred at room temperature for 2 daysand then the solvent was removed in vacuo. The residue was purified on asilica gel column using 30% ethyl acetate −70% hexane as eluant toafford 95 mg of white solid. NMR was consistent with the proposedstructure.

EXAMPLE 1 Synthesis ofβ-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]amino]phenyl]sulfonyl]amino]-benzenepropanoicacid, trifluoroacetate salt

A solution of the product from Example G (90 mg), 1,4 dioxane (2.5 ml)and 6N hydrochloric acid (2.5 ml) was stirred at room temperature for 17hours. The solvent was removed in vacuo and the residue was purified viareverse phase HPLC using a water (0.5% TFA) and acetonitrile gradient aseluant to afford 64 mg of white solid. NMR was consistent with theproposed structure.

Analysis Calculated for C₂₃H₂₃N₅O₅S ·2.5 CF₃CO₂H C, 43.87; H, 3.35; N,9.14; S, 4.18. Found: C, 43.45; H, 3.30; N, 9.16; S, 4.47.

The compounds of this invention and the following Examples 2-9 wereprepared according to the methodology that follows:

EXAMPLE H

General procedure for the following amino esters:

A slurry of 3-pyridinecarboxaldehyde (5.0 gm, 46.7 mmol), malonic acid(5.83 gm, 56 mmol), and ammonium acetate (4.32 gm, 56 mmol) inisopropanol (50 mL) was heated to reflux under a nitrogen atmosphere for2-3 hours. The reaction mixture was cooled to room temperature and thesolids collected by vacuum filtration. The solids were washed on thefilter with hot isopropanol (50 mL) and diethyl ether (50 mL) and thendried overnight under vacuum. The crude acid was dissolved in ethanol(50 mL) and anhydrous hydrogen chloride gas was passed through theethanol solution for 30 minutes. The reaction mixture was thenconcentrated in vacuo and the remaining white solids were trituratedwith diethyl ether (50 mL). The white solids were collected and driedunder vacuum to afford 5.85 gm (70%) of the amino ester. ¹H NMR wasconsistent with the expected product.

EXAMPLE I

Procedure for the following amino ester:

2-Pyridylacetic acid hydrochloride (10 gm, 57.6 mmol) was subjected tohydrogenation conditions (PtO₂ in AcOH solvent, 60 psi, 40° C.) toafford the piperidyl product 8.0 gm (80%). The resulting amino acid wassubjected to the above esterification conditions (Example H) to afford8.32 gm (90%) of product. ¹H NMR was consistent with the expectedproduct.

EXAMPLE J

The above compound was prepared using the methodology described inExample H.

EXAMPLE L

General procedure for the following aryl nitro compounds:

A solution of 3-nitrobenzenesulfonyl chloride (0.65 gm, 2.93 mmol) andthe corresponding amino ester prepared via methodology described inExamples H-J [prepared as described in J. Med. Chem., 1995, 38, 2378 orcommercially available] in methylene chloride (10 mL) was cooled to 0°C. under a nitrogen atmosphere. To the cooled suspension was then addedtriethylamine (0.82 mL, 5.86 mmol) and the reaction mixture was allowedto stir at 0° C. for 1 hour, then warmed to room temperature for 2hours. The reaction mixture was then transferred to a separatory funneland diluted with 20 mL water. After extraction, the isolated aqueouslayer was reextracted with methylene chloride (20 mL). The combinedorganic extracts were washed with brine (25 mL), dried over MgSO₄,vacuum filtered, and concentrated in vacuo to afford a crude whitesolid. The solids were triturated with 25% ethyl acetate in hexanes (50mL) and the resulting white crystals were collected and dried overnightunder vacuum. Final yield of product was 0.76 gm (79%). ¹H NMR wasconsistent with the expected product.

EXAMPLE M

General procedure for the following sulfonamides:

A solution of the nitro sulfonamide from Example L (0.40 gm, 1.23 mmol)and tin (II) chloride·2 H₂O in ethanol (25 mL) was heated to 80° C.under nitrogen for 2 hours. After cooling to room temperature thereaction mixture was poured into ice water (40 mL) and brought to abasic pH by the slow addition of saturated sodium bicarbonate solution(40 mL). The resulting mixture was then extracted twice with ethylacetate (2×30 mL). The combined organic extracts were then dried overMgSO₄, vacuum filtered, and concentrated in vacuo to afford the aminosulfonamide as an oily product (0.36 gm, 95%). No further purificationwas necessary. ¹H NMR was consistent with the expected product.

A solution of the compound from Example A (240 mg, 1.11 mmol) in DMAC (5mL) was cooled to −10° C. under a nitrogen atmosphere. To this solutionwas then added in sequence isobutyl chloroformate (0.15 mL, 1.17 mmol)followed by N-methyl morpholine (0.13 mL, 1.17 mmol). The resultingmixture was allowed to stir for 30 minutes at −10° C. In a separateflask the sulfonamide was dissolved in DMAC (5 mL) and then transferredto the reaction mixture via syringe. The resulting solution was allowedto warm to room temperature while stirring for 18 hours. The reactionmixture was concentrated in vacuo and the crude product was purified byHPLC to afford the above ester (45%, 284 mg). ¹H NMR was consistent withthe expected product.

The compounds of Examples 2-8 were prepared in the following manner.

A solution of the ethyl ester from Example N (230 mg, 0.40 mmol) inmethanol (2 mL), THF (2 mL), and 1 N NaOH (5 mL) was stirred for 2 hoursat 20° C. The reaction mixture was then concentrated in vacuo to afforda white residue. Purification of the crude product by HPLC (Method 1)afforded the acid as a white crystalline solid.

Yields:

Example 2 55%

Example 3 57%

Example 4 73%

Example 5 45%

Example 6 52%

Example 7 58%

Example 8 60%

EXAMPLE 2 (±)3-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-carbonyl]amino]phenyl]sulfonyl]amino]-4-pentynoicacid

¹H NMR (DMSO) δ12.25 (s, 1H), 10.28 (s, 1H), 10.0 (s, 1H), 8.18 (d, 1H),8.16 (s, 1H), 8.03 (d, 1H), 7.9 (d, 1H), 7.8 (s, 1H), 7.6 (m, 5H), 7.45(d, 1H), 4.25 (m, 1H), 3.45 (m, 1H), 3.05 (s, 1H), 2.58 (d, 2H).¹³C NMR (DMSO) 164.8, 155.8, 144.4, 139.4, 135.7, 129.9, 129.5, 127.8,125.6, 123.7, 121.9, 118.2, 74.7, 41.8, 41.4, 40.0 Hz.Analysis Calc'd for C₁₉H₁₉N₅O₅S·1.15 TFA C, 46.41; H, 3.71; N, 12.89Found: C, 45.67; H, 3.59; N, 12.40

EXAMPLE 3 (±)3-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-carbonyl]amino]phenyl]sulfonyl]amino]-4-pentenoicacid, trifluoroacetate salt

¹H NMR (DMSO) δ12.25 (s, 1H), 10.57 (s, 1H), 10.02 (s, 1H), 8.33 (s,1H), 8.0 (d, 1H), 7.97 (d, 1H), 7.86 (s, 1H), 7.60 (m, 5H), 7.58 (t,1H), 7.55 (t, 1H), 7.46 (d, 1H), 5.55 (m, 1H), 4.95 (d, 1H), 4.89 (d,1H), 4.05 (m, 1H), 2.38 (m, 2H).¹³C NMR (DMSO) 171.2, 164.8, 155.8, 142.1, 139.4, 137.0, 135.7, 129.9,129.5, 127.8, 125.6, 123.7, 123.5, 121.6, 118.1, 115.7 Hz.Analysis Calc'd for C₁₉H₂₁N₅O₅S·1.3 TFA C, 44.75; H, 3.88; N, 12.08Found: C, 44.94; H, 3.65; N, 12.07

EXAMPLE 4 (±)β-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-carbonyl]amino]phenyl]sulfonyl]amino]-3,5-dichlorobenzenepropanoic acid, trifluoroacetate salt

¹H NMR (DMSO) δ10.40 (s, 1H), 9.80 (s, 1H), 8.43 (d, 1H), 8.10 (s, 1H),7.90 (d, 1H), 7.85 (d, 1H), 7.60 (t, 1H), 7.50 (m, 5H), 7.39 (t, 1H),7.30 (d, 1H), 7.22 (t, 1H), 7.14 (d, 2H), 4.62 (m, 1H), 2.60 (m, 2H).¹³C NMR (DMSO) 170.63, 164.65, 155.8, 144.0, 141.0, 139.3, 135.8, 135.6,133.6, 129.8, 129.0, 127.8, 126.7, 125.7, 123.8, 123.1, 117.8, 53.9,41.8 Hz.Analysis Calc'd for C₂₃H₂₁Cl₂N₅O₅S·1.2 TFA C, 44.39; H, 3.26; N, 10.19Found: C, 44.39; H, 2.92; N, 10.19

EXAMPLE 5β-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-carbonyl]amino]phenyl]sulfonyl]amino]pyridine-3-propanoicacid, tris(trifluoroacetate) salt

¹H NMR (DMSO) δ10.22 (s, 1H), 10.0 (s, 1H), 8.58 (d, 1H), 8.45 (s, 1H),8.42 (d, 1H), 8.15 (s, 1H), 7.90 (d, 1H), 7.85 (m, 2H), 7.60 (m, 4H),7.47 (d, 1H), 7.37 (m, 3H), 4.75 (m, 1H), 2.77 (m, 2H).¹³C NMR (DMSO) 170.6, 164.7, 155.8, 141.4, 139.3, 135.7, 129.9, 129.4,127.8, 125.6, 124.3, 123.4, 121.4, 118.0, 52.1, 41.4 Hz.Analysis Calc'd for C₂₂H₂₃N₆O₅S·3.0 TFA·1.0 H₂O C, 39.87; H, 3.35; N,9.96 Found: C, 39.84; H, 3.02; N, 10.24

EXAMPLE 61-[[3-[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]-amino]phenyl]sulfonyl]piperidine-2-aceticacid, trifluoroacetate salt

¹H NMR (DMSO) δ10.58 (s, 1H), 10.03 (s, 1H), 8.30 (s, 1H), 8.06 (d, 1H),7.90 (d, 1H), 7.85 (s, 1H), 7.60 (m, 5H), 7.56 (d, 1H), 7.52 (d, 1H),7.45 (d, 1H), 4.35 (m, 1H), 3.0 (t, 1H), 2.7 (dd, 1H), 2.28 (dd, 1H),1.45 (m, 6H), 1.15 (2H).Analysis Calc'd for C₂₁H₂₅N₅O₅S·1.4 TFA C, 46.17; H, 4.30; N, 11.31Found: C, 46.02; H, 4.30; N, 11.32

EXAMPLE 73S-[[[3-[[[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]-phenyl]carbonyl]amino]phenyl]sulfonyl]amino]-4-pentynoicacid, trifluoroacetate salt

¹H NMR (DMSO) δ12.53 (s, 1H), 10.7 (s, 1H), 10.6 (s, 1H), 8.49 (s, 2H),8.38 (d, 1H), 8.34 (s, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.86 (s, 1H),7.63 (d, 1H), 7.59 (d, 1H), 7.57 (s, 4H), 7.47 (d, 1H), 4.28 (m, 1H),3.02 (s, 1H), 2.58 (d, 2H).Analysis Calc'd for C₂₁H₂₁N₅O₅S·1.3 TFA C, 46.95; H, 3.72; N, 11.60Found: C, 46.87; H, 3.61; N, 11.83

EXAMPLE 83-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-carbonyl]amino]phenyl]sulfonyl]amino]-4-pentynoicacid, trifluoroacetate salt

Analysis Calc'd for C₁₉H₁₉N₅O₅S·1.3 TFA C, 44.91; H, 3.54; N, 12.12Found: C, 44.90; H, 3.40; N, 12.34

EXAMPLE AA

By utilizing the same procedure as described in Example E, the productfrom Example F was coupled with 3-nitrobenzene sulfonyl chloride toafford the above compound.

NMR data was consistent with the proposed structure.

EXAMPLE BB

The product from Example AA was hydrogenated and purified in the samemanner as described in Example F.

NMR data was consistent with the proposed structure.

EXAMPLE CC

To a solution of the product from Example BB, 1.2 equivalents ofbis-t-butoxycarbonyl thiourea and 2.2 equivalents of triethylamine inDMF at 0° under nitrogen was added 1.2 equivalents mercuric chloride inone portion. The reaction was stirred for 30 minutes at 0° and then 30minutes at room temperature. The reaction was quenched with ethylacetate, stirred for 30 minutes, and then filtered and concentrated. Thecrude product was purified on a silica gel column eluting with 25% ethylacetate—75% hexane to afford the product.

NMR data was consistent with the proposed structure.

EXAMPLE 9β-[[[3-[[[3-[(aminoiminomethyl)amino]phenyl]-sulfonyl]amino]phenyl]sulfonyl]amino]phenyl-propanoicacid, trifluoroacetate salt

The product from Example CC was treated and purified in the same fashionas described in Example 1.

NMR data was consistent with the proposed structure.

Analysis Calc'd for C₂₂H₂₃N₅O₆S₂·1.5 CF₃CO₂H: C, 43.61; H, 3.59; N,10.17; S, 9.31 Found: C, 43.71; H, 3.46; N, 10.34; S, 9.65

The activity of the compounds of the present invention was tested in thefollowing assays. The results of testing in the assays are tabulated inTable 1.

Vitronectin Adhesion Assay

Materials

Human vitronectin receptor (α_(v)β₃) was purified from human placenta aspreviously described [Pytela et al., Methods in Enzymology, 144:475-489(1987)]. Human vitronectin was purified from fresh frozen plasma aspreviously described [Yatohgo et al., Cell Structure and Function,13:281-292 (1988)]. Biotinylated human vitronectin was prepared bycoupling NHS-biotin from Pierce Chemical Company (Rockford, Ill.) topurified vitronectin as previously described [Charo et al., J. Biol.Chem., 266(3):1415-1421 (1991)]. Assay buffer, OPD substrate tablets,and RIA grade BSA were obtained from Sigma (St. Louis, Mo.). Anti-biotinantibody was obtained from Calbiochem (La Jolla, Calif.). Linbromicrotiter plates were obtained from Flow Labs (McLean, Va.). ADPreagent was obtained from Sigma (St. Louis, Mo.).

Methods

Solid Phase Receptor Assays

This assay was essentially the same as previously reported [Niiya etal., Blood, 70:475-483 (1987)]. The purified human vitronectin receptor(α_(v)β₃) was diluted from stock solutions to 1.0 μg/mL in Tris-bufferedsaline containing 1.0 mM Ca⁺⁺, Mg⁺⁺, and Mn⁺⁺, pH 7.4 (TBS⁺⁺⁺). Thediluted receptor was immediately transferred to Linbro microtiter platesat 100 μL/well (100 ng receptor/well). The plates were sealed andincubated overnight at 4° C. to allow the receptor to bind to the wells.All remaining steps were at room temperature. The assay plates wereemptied and 200 μL of 1% RIA grade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were addedto block exposed plastic surfaces. Following a 2 hour incubation, theassay plates were washed with TBS⁺⁺⁺ using a 96 well plate washer.Logarithmic serial dilution of the test compound and controls were madestarting at a stock concentration of 2 mM and using 2 nM biotinylatedvitronectin in TBS⁺⁺⁺/BSA as the diluent. This premixing of labeledligand with test (or control) ligand, and subsequent transfer of 50 μLaliquots to the assay plate was carried out with a CETUS Propette robot;the final concentration of the labeled ligand was 1 nM and the highestconcentration of test compound was 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells were washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody was diluted 1:3000 in TBS⁺⁺⁺/BSA and 125 μL wereadded to each well. After 30 minutes, the plates were washed andincubated with OPD/H₂O₂ substrate in 100 mM/L Citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ were recorded for analysis. The data wereanalyzed using a macro written for use with the EXCELS spreadsheetprogram. The mean, standard deviation, and % CV were determined forduplicate concentrations. The mean A₄₅₀ values were normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values were subjected to a four parameter curve fit algorithm[Rodbard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)],plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding ofbiotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[[2-[[5-[(aminoiminomethyl]amino]-1-oxopentyl]amino]-1-oxoethyl)amino]-3-pyridinepropanoicacid [U.S. Ser. No. 08/375,338, Example 1] which is a potent α_(v)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

Purified IIb/IIIa Receptor Assay

Materials

Human fibrinogen receptor (α_(IIb)β₃) was purified from outdatedplatelets. (Pytela, R., Pierschbacher, M. D., Argraves, S., Suzuki, S.,and Rouslahti, E. “Arginine-Glycine-Aspartic acid adhesion receptors”,Methods in Enzymology 144(1987):475-489.) Human vitronectin was purifiedfrom fresh frozen plasma as described in Yatohgo, T., Izumi, M.,Kashiwagi, H., and Hayashi, M., “Novel purification of vitronectin fromhuman plasma by heparin affinity chromatography,” Cell Structure andFunction 13(1988):281-292. Biotinylated human vitronectin was preparedby coupling NHS-biotin from Pierce Chemical Company (Rockford, Ill.) topurified vitronectin as previously described. (Charo, I. F., Nannizzi,L., Phillips, D. R., Hsu, M. A., Scarborough, R. M., “Inhibition offibrinogen binding to GP IIb/IIIa by a GP IIIa peptide”, J. Biol. Chem.266(3)(1991): 1415-1421.) Assay buffer, OPD substrate tablets, and RIAgrade BSA were obtained from Sigma (St. Louis, Mo.). Anti-biotinantibody was obtained from Calbiochem (La Jolla, Calif.). Linbromicrotiter plates were obtained from Flow Labs (McLean, Va.). ADPreagent was obtained from Sigma (St. Louis, Mo.).

Methods

Solid Phase Receptor Assays

This assay is essentially the same reported in Niiya, K., Hodson, E.,Bader, R., Byers-Ward, V. Koziol, J. A., Plow, E. F. and Ruggeri, Z. M.,“Increased surface expression of the membrane glycoprotein IIb/IIIacomplex induced by platelet activation: Relationships to the binding offibrinogen and platelet aggregation”, Blood 70(1987):475-483. Thepurified human fibrinogen receptor (α_(IIb)β₃) was diluted from stocksolutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺,Mg⁺⁺, and Mn⁺⁺, pH 7.4 (TBS⁺⁺⁺). The diluted receptor was immediatelytransferred to Linbro microtiter plates at 100 μL/well (100 ngreceptor/well). The plates were sealed and incubated overnight at 4° C.to allow the receptor to bind to the wells. All remaining steps were atroom temperature. The assay plates were emptied and 200 μL of 1% RIAgrade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were added to block exposed plasticsurfaces. Following a 2 hour incubation, the assay plates were washedwith TBS⁺⁺⁺ using a 96 well plate washer. Logarithmic serial dilution ofthe test compound and controls were made starting at a stockconcentration of 2 mM and using 2 nM biotinylated vitronectin inTBS⁺⁺⁺/BSA as the diluent. This premixing of labeled ligand with test(or control) ligand, and subsequent transfer of 50 μL aliquots to theassay plate was carried out with a CETUS Propette robot; the finalconcentration of the labeled ligand was 1 nM and the highestconcentration of test compound was 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells were washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody was diluted 1:3000 in TBS⁺⁺⁺/BSA and 125 μL wereadded to each well. After 30 minutes, the plates were washed andincubated with ODD/H₂O₂ substrate in 100 mM/L citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ were recorded for analysis. The data wereanalyzed using a macro written for use with the EXCEL™ spreadsheetprogram. The mean, standard deviation, and % CV were determined forduplicate concentrations. The mean A₄₅₀ values were normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values were subjected to a four parameter curve fitalgorithm, [Robard et al., Int. Atomic Energy Agency. Vienna, pp 469(1977)], plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding ofbiotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Ser. No. 08/375,338, Example 1] which is a potent α_(v)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

Human Platelet Rich Plasma Assays

Healthy aspirin free donors were selected from a pool of volunteers. Theharvesting of platelet rich plasma and subsequent ADP induced plateletaggregation assays were performed as described in Zucker, M. B.,“Platelet Aggregation Measured by the Photometric Method”, Methods inEnzymology 169(1989):117-133. Standard venipuncture techniques using abutterfly allowed the withdrawal of 45 mL of whole blood into a 60 mLsyringe containing 5 mL of 3.8% trisodium citrate. Following thoroughmixing in the syringe, the anti-coagulated whole blood was transferredto a 50 mL conical polyethylene tube. The blood was centrifuged at roomtemperature for 12 minutes at 200×g to sediment non-platelet cells.Platelet rich plasma was removed to a polyethylene tube and stored atroom temperature until used. Platelet poor plasma was obtained from asecond centrifugation of the remaining blood at 2000×g for 15 minutes.Platelet counts are typically 300,000 to 500,000 per microliter.Platelet rich plasma (0.45 mL) was aliquoted into siliconized cuvettesand stirred (1100 rpm) at 37° C. for 1 minute prior to adding 50 uL ofpre-diluted test compound. After 1 minute of mixing, aggregation wasinitiated by the addition of 50 uL of 200 uM ADP. Aggregation wasrecorded for 3 minutes in a Payton dual channel aggregometer (PaytonScientific, Buffalo, N.Y.). The percent inhibition of maximal response(saline control) for a series of test compound dilutions was used todetermine a dose response curve. All compounds were tested in duplicateand the concentration of half-maximal inhibition (IC₅₀) was calculatedgraphically from the dose response curve for those compounds whichexhibited 50% or greater inhibition at the highest concentration tested;otherwise, the IC₅₀ is reported as being greater than the highestconcentration tested. AvB3 IIb/IIIa IC50 IC50 Human PRP Example (nM)(nM) (μM) 1 1.66 11.3 >200 μM 2 35.1 353 3 5.34 11.6 4 659 987 5 4.6624.7 6 183 3920 7 15.0 418 8 11.3 38.2 9 29.3 93.6

1-26. (canceled)
 27. A method for treating diabetic retinopathy in amammal in need of such treatment, wherein: the method comprisesadministering an effective α_(v)β₃ inhibiting amount comprising fromabout 0.01 mg to about 1000 mg per kilogram of body weight of a compoundor pharmaceutically acceptable salt thereof to the mammal; the compoundcorresponds in structure to the formula:

B is selected from the group consisting of —CONR⁵⁰— and —SO₂NR⁵⁰—; A isselected from the group consisting of:

Y¹ is selected from the group consisting of N—R², O, and S; as to R²: R²is selected from the group consisting of H; alkyl; aryl; hydroxy;alkoxy; cyano; nitro; amino; alkenyl; alkynyl; alkyl substituted withone or more substituents selected from the group consisting of loweralkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino,alkoxy, aryl, aryl substituted with one or more halogen, haloalkyl,lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl,amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles, and fused monocyclic heterocycles; arylsubstituted with one or more substituents selected from the groupconsisting of halogen, haloalkyl, hydroxy, lower alkyl, alkoxy,methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl,sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fusedaryl, monocyclic heterocycles, and fused monocyclic heterocycles;monocyclic heterocycles; and monocyclic heterocycles substituted withone or more substituents selected from the group consisting of halogen,haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxylderivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,sulfonamide, aryl, and fused aryl; or R² and R⁷, together with the atomsto which they are bonded, form: a 4-12 membered dinitrogen containingheterocycle optionally substituted with one or more substituentsselected from the group consisting of lower alkyl, hydroxy, and phenyl;a 5 membered heteroaromatic ring; or a 5 membered heteroaromatic ringfused with a phenyl group; as to R⁷: R⁷ is selected from the groupconsisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl;bicycloalkyl; aryl; acyl; benzoyl; alkyl substituted with one or moresubstituents selected from the group consisting of lower alkyl, halogen,hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy,thio, alkylthio, sulfonyl, aryl, aralkyl, aryl substituted with one ormore substituents selected from the group consisting of halogen,haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles; aryl substituted with one or more substituentsselected from the group consisting of halogen, haloalkyl, lower alkyl,alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano,alkylthio, alkylsulfonyl, aryl, and fused aryl; monocyclic and bicyclicheterocyclicalkyls; —SO₂R¹⁰; and

R⁷ and R⁸, together with the nitrogen to which they are bonded, form a4-12 membered mononitrogen containing monocyclic or bicyclic ring,wherein the ring: is optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, carboxylderivatives, aryl, and hydroxy; and optionally contains (in addition tothe nitrogen) a heteroatom selected from the group consisting of O, N,and S; or R⁷ and R², together with the atoms to which they are bonded,form: a 4-12 membered dinitrogen containing heterocycle optionallysubstituted with one or more substituents selected from the groupconsisting of lower alkyl, hydroxy, and phenyl; a 5 memberedheteroaromatic ring; or a 5 membered heteroaromatic ring fused with aphenyl group; as to R⁸: R⁸ is selected from the group consisting of H;alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl;benzoyl; alkyl substituted with one or more substituents selected fromthe group consisting of lower alkyl, halogsen, hydroxy, haloalkyl,cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio,sulfonyl, aralkyl, aryl optionally substituted with one or moresubstituents selected from the group consisting of halogen, haloalkyl,lower alkyl, alkoxy, methylenedioxy. ethylenedioxy, alkylthio,haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives,aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles; aryl substituted with one or more substituentsselected from the group consisting of halogen, haloalkyl, lower alkyl,alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano,alkylthio, alkylsulfonyl, aryl, and fused aryl; monocyclic and bicyclicheterocyclicalkyls; —SO₂R¹⁰; and

or R⁸ and R⁷, together with the nitrogen to which they are bonded, forma 4-12 membered mononitrogen containing monocyclic or bicyclic ring,wherein the ring: is optionally substituted with one or moresubstituents selected from the group consisting of lower alkyl, carboxylderivatives, aryl, and hydroxy; and optionally contains (in addition tothe nitrogen) a heteroatom selected from the group consisting of O, N,and S; R¹⁰ is selected from the group consisting of alkyl, aryl, andmonocyclic heterocycles, wherein: any such group is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, haloalkyl alkyl, alkoxy, cyano, nitro, amino,acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl,alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio,trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio,alkylthio, and monocyclic heterocycles; R⁵ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenylethyl; or asto Y²and R^(7A): Y² and R^(7A) are independent substituents such that:Y² is selected from the group consisting of alkyl; cycloalkyl;bicycloalkyl; aryl; monocyclic heterocycles; alkyl substituted with arylwhich can also be optionally substituted with one or more substituentsselected from the group consisting of halo, haloalkyl, alkyl, nitro,hydroxy, alkoxy, aryloxy, aryl, and fused aryl; aryl substituted withone or more substituents selected from the group consisting of halo,haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro,methylenedioxy, ethylenedioxy, and alkyl; alkynyl; alkenyl; —SR⁹. and—OR⁹—; and R^(7A) is selected from the group consisting of H; alkyl;alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl;benzoyl; alkyl substituted with one or more substituents selected fromthe group consisting of lower alkyl, halogen, hydroxy, haloalkyl, cyano,nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl,aryl, aralkyl, aryl substituted with one or more substituents selectedfrom the group consisting of halogen, haloalkyl, lower alkyl, alkoxy,methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy,cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino,alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl,alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl,fused aryl, monocyclic heterocycles; aryl substituted with one or moresubstituents selected from the group consisting of halogen, haloalkyl,lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxylderivatives, cyano, alkylthio, alkylsulfonyl, aryl, and fused aryl;monocyclic and bicyclic heterocyclicalkyls; —SO₂R¹⁰; and

Y² is —SR⁹ and —OR⁹— such that R^(7A) and R⁹, together with the atoms towhich they are bonded, form a 4-12 membered mononitrogen containingsulfur or oxygen containing heterocyclic ring; or Y² is carbon such thatY² and R^(7A), together with the atoms to which they are bonded, form a4-12 membered mononitrogen containing ring optionally substituted withalkyl, aryl, or hydroxy; as to R⁹: R⁹ is selected from the groupconsisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R⁹ andR^(7A), together with the atoms to which they are bonded, form a 4-12membered mononitrogen containing sulfur or oxygen containingheterocyclic ring; Z¹, Z², Z⁴, and Z⁵ are independently selected fromthe group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; arylalkoxy;halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino;dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives;acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles;fused monocyclic heterocycles; and A; R⁵⁰ is selected from the groupconsisting of H and alkyl; R¹ is selected from the group consisting ofH, alkyl, alkenyl, alkynyl, aryl, and aryl, optionally substituted withone or more substituents selected from the group consisting of halogen,haloalkyl, hydroxy, alkoxy, aryloxy, aralkoxy, amino, aminoalkyl,carboxyl derivatives, cyano, and nitro; t is zero, 1, or 2; R is X—R³; Xis selected from the group consisting of O, S, and NR⁴; R³ and R⁴ areindependently selected from the group consisting of hydrogen; alkyl;alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; and steroids; andY³ and Z³ are independently selected from the group consisting of H,alkyl, aryl, cycloalkyl, and aralkyl.
 28. A method according to claim27, wherein the compound corresponds in structure to Formula II:


29. A method according to claim 28, wherein A is:


30. A method according to claim 28, wherein A is:


31. A method according to claim 27, wherein the compound corresponds instructure to Formula III:


32. A method according to claim 31, wherein A is:


33. A method according to claim 31, wherein A is:


34. A method according to claim 27, wherein A is:


35. A method according to claim 27, wherein A is: